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Nonalcoholic fatty liver disease
Copyright © 2004: Mexican Association of Hepatology
ANNALS OF HEPATOLOGY
Number 3 July-September 2 0 0 4
Volume 3
Lafaine MG et al. Nonalcoholic fatty liver disease 93
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Annals of Hepatology 2004; 3(3): July-September: 93-99
Annals of Hepatology
Abstract
Nonalcoholic fatty liver disease is a clinicopathologic syndrome that encompasses several clinical entities. The spectrum of conditions ranges from simple ste-atosis to steatohepatitis, fibrosis and end stage liver disease. The condition was originally described in obese, diabetic, middle-aged females without a history of significant alcohol use with liver histology consis-tent with alcoholic hepatitis.1,2 It is known that this
en-tity occurs without any particular sex predilection, in lean individuals,3 as well as an increasing number of
obese children.4
Other terms have been used to describe this clinical entity such as alcohol-like hepatitis, pseudo-alcoholic hepatitis, diabetic hepatitis and steatonecrosis. Lud-wig and colleagues introduced the term nonalcoholic steatohepatitis (NASH) to describe patients fitting the picture of alcoholic hepatitis but without a history of significant alcohol abuse.2 The term nonalcoholic fatty
liver disease (NAFLD) is used more frequently to in-clude the spectrum of conditions that range from ste-atosis through steatohepatitis, fibrosis and cirrhosis. NASH is reserved for patients with steatohepatitis and fibrosis.
NAFLD is now being recognized as the most common cause of elevated liver enzymes in the United States. Although the exact etiology of NAFLD is not known, it may be caused by insulin resistance coupled with in-creased oxidative stress to the hepatocytes. No specif-ic therapy has been approved for this condition and the mainstay of management is weight loss.
Key words: Nonalcoholic steatohepatitis, liver, obesi-ty, fatty liver.
Introduction
Nonalcoholic fatty liver disease is often associated with obesity, type II diabetes mellitus and dyslipidemia, and is often regarded as the hepatic manifestation of the metabolic syndrome-the condition of dyslipidemia,
hy-Consice Review
Nonalcoholic fatty liver disease
Lafaine M. Grant;1 Mauricio Lisker-Melman1
1Division of Gastroenterology. Hepatology Program.
Address for correspondence:
Mauricio Lisker-Melman MD, Division of Gastroenterology. Hepatology Program. Washington University School of Medicine. 660 S. Euclid Ave. PO Box 8124. St. Louis MO 63110.
pertension, obesity and diabetes.5 Disease severity may be
classified according to histologic findings. Some patients with NAFLD have simple hepatic steatosis without any associated inflammation or fibrosis. Others, with the more advanced form, have a combination of steatosis with either/or nonspecific inflammation, ballooning de-generation of the hepatocytes, fibrosis and Mallory bod-ies. This latter group is classified as NASH.6,7
It must be acknowledged that there are other second-ary causes of hepatic steatosis such as drugs (corticoster-oids, amiodarone, synthetic estrogens, etc.), rapid weight loss, surgical procedures (jejunoileal bypass or extensive small bowel resection) and miscellaneous causes such as TPN and diverticulosis,7 (see table I). This review will
focus on nonalcoholic fatty liver disease without any oth-er associated factor.
Epidemiology
NAFLD is a worldwide phenomenon spanning all the continents.7 The exact prevalence is uncertain. In one
study, 126 candidates for adult-to-adult living donor liver transplant underwent liver biopsy as part of the pre-trans-plant evaluation. Twenty percent were found to have fat-ty liver which made them ineligible donors.8 Another
study that reviewed liver histology of 503 consecutive fa-tal traffic accident victims and 423 aircrew fafa-talities, found that the prevalence of steatosis (NAFLD) was 24% and 15.6% respectively. In this series, the prevalence of steatosis associated with inflammation and fibrosis (NASH) was 3%.9,10
Over the last several decades, obesity – defined as body-mass index > 30 kg/m2, has emerged as a major
medical problem,11,12 Current data indicate that the
preva-lence of obesity among US adults was 20.9% in 2001 (a 74% increase since 1991). The prevalence of those with diabetes increased to 7.9% in 2001(a 61% increase since 1990).13 These numbers are believed to underrepresent
the true extent of the problem. We know that obesity is often associated with insulin resistance, diabetes, and hy-perlipidemia.14,15 One autopsy series of 351
non-alcohol-ics found a prevalence of steatohepatitis of 2.7% in lean versus 18.5% in markedly obese patients. Severe fibrosis was found in 6.6% of lean and 13.8% of markedly obese individuals. This may be explained by the higher preva-lence of diabetes in the obese group.16 Other published
Annals of Hepatology 3(3) 2004: 93-99
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from 40% to 75% has been reported in patients withNASH.6,18 Given the close association of NAFLD with
obesity and diabetes, this substantial increase in their prevalence portends an increase in the cases of NAFLD in the future. One must bear in mind however, that popula-tions other than obese, diabetic, middle-aged women are at risk for developing steatosis and NASH. This was dem-onstrated in a study of the clinical profile of a group of patients with NASH. Of those studied, 19 of 33 patients (58%) were male and 26 of 33 patients (79%) had normal glucose levels.3
In addition, the increase in the number of cases of NAFLD in children and adolescents appear to be in paral-lel to the adult condition since the earliest reported case in 1983.19,20 Interestingly, it is noted that NAFLD is more
frequent in young boys than girls and tends to occur where there is a family history of diabetes and obesity.4
Clinical presentation
Most patients with NAFLD are asymptomatic. Many are discovered when elevated transaminases are detected on routine laboratory tests or during evaluation for other conditions such as obesity, diabetes, hyperlipidemia or hypertension. Symptoms are usually non-specific when they occur. Some patients have fatigue, malaise, or vague right upper quadrant pain. Obesity is the most common finding on physical exam and hepatomegaly is the most common sign of liver disease.21 Stigmata of chronic liver
disease such as spider nevi, palmar erythema, jaundice, gynecomastia, asterixis and muscle wasting are typically not seen until the later stages of the disease.
Diagnosis
There are a number of prerequisite criteria to fulfill in order to entertain the diagnosis of NAFLD. As the name implies, patients under consideration must lack a history of significant alcohol use. Studies show that as little as 20 to 30 g of daily alcohol intake can lead to alcohol induced liver disease.22,23 In addition, one must ideally rule out
other primary liver diseases or any other secondary caus-es of NAFLD. In some patients, NAFLD or NASH may be superimposed on other liver diseases (i.e. viral hepati-tis, autoimmune liver disease).
Laboratory assessment
No single laboratory test can diagnose NAFLD or ac-curately differentiate between the different stages from steatosis to full-blown NASH. The most common labora-tory abnormality is an elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST).24 The
ele-vation rarely exceeds 2 to 3 times the upper limits of nor-mal values. The pattern of aminotransferase elevation may be helpful to distinguish NAFLD from alcoholic liv-er disease. The ALT/AST ratio is usually < 1 in NAFLD and in alcoholic liver disease AST is predominantly ele-vated. An AST/ALT ratio > 1 is more indicative of fibro-sis and advanced disease. Generally the alkaline phos-phatase and gamma-glutamyl transferase (GGT) are nor-mal or mildly elevated. Serum albumin, prothrombin time and bilirubin are usually normal until the later stages of the disease.
Radiologic assessment
Current routine imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) are reliable, non-invasive methods of evaluating fatty liv-er disease.
Criteria for detecting the fatty liver on ultrasound in-clude the brightness of the liver in comparison to the kid-ney (liver kidkid-ney contrast), vascular blurring (obscuring the hepatic vein trunk) and deep attenuation (intensity of the echo beam in the right hepatic lobe). With well ap-plied and standardized ultrasonographic criteria, fatty liv-er was diagnosed with a sensitivity of 83% and a specific-ity of 100%.25 However, this required fatty changes in at
least 30% of the liver.
Computerized tomography (CT) imaging determines the presence of fatty liver when the liver minus the spleen attenuation is less than -10 Hounsfield units. Based on this criterion, unenhanced CT remains the most accurate method for detecting steatosis.26
One study found that unenhanced CT had a sensitivity of 93% and a positive predictive value of 76% when one third of the liver had fatty infiltration.27
MRI takes advantage of the characteristic differences in resonant frequencies between fat and water. Signal in-tensity is at a maximum when the signals of fat and water are in phase. As such, the fatty liver has higher signal in-tensity on in-phase images and a loss of signal inin-tensity on out-of phase image.28 When compared to the spleen,
the fatty liver appears darker on magnetic resonance im-aging. MRI may more readily differentiate between focal fat versus a focal mass, otherwise it offers no advantage
Table I. Secondary causes of hepatic steatosis.
Surgical procedures Jejunoileal bypass
Extensive small bowel resection
Drugs Amiodarone
Choroquine Perhexiline Corticosteroids Synthetic estrogen
Medical conditions Inflammatory bowel disease
Weber-Christian disease Acute fatty liver of pregnancy
Miscellaneous TPN
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A. B.
Figure 1. Hematoxylin and eosin stain showing predominantly macrovesicular steatosis (A) and an enlarged view showing steatosis, ballooning
changes (arrows), and lobular inflammation (B). (C) Hematoxylin and eosin stain highlighting Mallory bodies (arrows). (D) Masson trichrome stain hig-hlighting extensive sinusoidal fibrosis (arrowhead). Slides courtesy of Hanlin L. Wang, MD, PhD. Asst Professor. Dept. of Pathology & Immunology, Was-hington University School of Medicine.
C. D.
Demographic Steatosis NASH
General population 16-23% 2-3%
Obese 65-85% 19%
Severely obese (BMI > 40 kg/m2) > 90% ~ 50%
Diabetic 21-78% 35%
Prevalence estimates of steatosis and NASH in various populations.
Steatosis NASH
Obese – 38 million with NAFLD 29.6 million 8.4 million
Diabetes – 7.8 million with NAFLD 4.0 million 3.8 million
Population projection for the year 2020 if obesity and diabetes trends continue.
over CT imaging and is less readily available and more expensive.
Magnetic resonance spectroscopy (MRS) is the only imaging modality that offers some quantitative measure-ment of hepatic fat content. In one study, MRS was shown to correlate well with histologic grading of fatty infiltration of the liver.29 In another study, MRS
accurate-ly assessed hepatic trigaccurate-lyceride content in 15 patients.30
MRS is not readily available for routine clinical use; its accuracy and reproducibility improve when fatty infiltra-tion is diffuse throughout the liver.
Annals of Hepatology 3(3) 2004: 93-99
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were directly compared in patients with biopsy-proven NAFLD, no modality was able to distinguish only steato-sis from more advance stages that include inflammation or fibrosis. Steatosis was the only pathological feature de-tected radiologically.27
Pathology
The histologic examination of the liver remains the gold standard for NAFLD diagnosis.
The histopathologic lesions required for the diagnosis of NASH include; macrovesicular steatosis and one or all of the following: a mixed, lobular inflammatory infiltrate, hepatocellular ballooning, typically in zone 3. The fol-lowing features are supportive but are not absolutely nec-essary for the diagnosis: perisinusoidal fibrosis and Mal-lory’s hyaline in zone 3.31
Some variability in the interpretation of histologic pa-rameters still exists. One study addressed this issue in a review of 19 histologic features of NAFLD. Four liver pathologists reviewed liver biopsy specimens of patients with NAFLD. The interobserver and intraobserver cordance were documented. Moderate to substantial con-cordance for features such as extent of steatosis, location and grade of fibrosis, ballooning degeneration, hepato-cyte necrosis and Mallory bodies was found. There was poor concordance in the assessment of inflammation.32 In
an effort to standardize the evaluation, a grading and staging system of the histologic features of NASH has been proposed. This system takes into consideration the grade of inflammation as well as the stage of fibrosis.33
Grading of inflammation considers such variables as macrovesicular steatosis, hepatocytes ballooning, lobular versus portal inflammation and Mallory’s hyaline. Fibro-sis was staged according to the extent of perisinusoidal, portal or bridging extension.
Natural history
The natural history of NAFLD varies according to his-tologic stage. NAFLD is generally regarded as a condi-tion with an indolent course.
One study followed the course of 40 patients with ste-atosis only, over a median of 11 years. None had pro-gressed to cirrhosis (one propro-gressed to fibrosis) and none died of liver-related illnesses.34 In other instances, up to
16% of patients with NAFLD present with more advance stages, with either fibrosis or cirrhosis.1,3,18,35 Outcome is
generally worse for patients detected with fibrosis, bal-looning degeneration or necrosis on liver biopsy. In one study comparing patients with fatty liver and inflamma-tion versus fibrosis and necrosis, more subjects in the lat-ter group developed cirrhosis (24% versus 3%) and liver-related deaths (30% versus 5%).36 Therefore, it is
impor-tant to develop methods to detect or predict which patients may have a benign course versus those at risk for
progression to end stage liver disease. Reliable prediction may also help to determine when to perform a liver biop-sy, when to start “specific” management or establish an accurate prognosis.
In an attempt to identify predictors of fibrosis, one group investigated 144 patients with NAFLD. Older age, obesity, diabetes and ALT/AST ratio > 1 were significant predictors of severe liver fibrosis.35 In another study,
in-sulin resistance and hypertension were independent pre-dictors of advanced NAFLD in severely obese subjects.37
This subgroup of patients may benefit the most from a liver biopsy.
The incidence of hepatocellular carcinoma (HCC) has increased in the United States. This has been attributed to its association with hepatitis B and hepatitis C infection.38
However, with the increased incidence of obesity and di-abetes, NAFLD may emerge as an important precursor to cirrhosis and therefore, HCC. One recent study examined the role of NAFLD in the development of HCC. Of 105 consecutive patients with HCC, 13% had a prior diagno-sis of NASH or clinical features condiagno-sistent with NAFLD.39 Another series followed 82 NASH patients
over a decade. About 7% had progressed to cirrhosis and HCC.40 A recent retrospective analysis of patients with
HCC, found that 4% (half of those with cryptogenic cir-rhosis being followed at study time) had features consis-tent with NAFLD.41 Larger prospective studies are
neces-sary to validate the association of NAFLD and HCC. If the results of the initial smaller studies are validated, rou-tine screening for HCC may be indicated for patients with cirrhosis secondary to NASH.
Pathogenesis
The pathogenesis of nonalcoholic fatty liver disease remains poorly understood. It is a complex, multifactorial process that involves genetic and environmental ele-ments.42,43
In 1998, a “two-hit” hypothesis was proposed to ex-plain the pathogenesis of NAFLD, based on existing hu-man and animal studies.44 According to this proposal, the
first “hit” is the accumulation of fat in the liver. Once the liver shows fatty infiltration, a second “hit” triggers the progression from steatosis to steatohepatitis. Initially the first hit was considered to be insulin resistance. Recently, this concept has been expanded to also include unknown genetic factors and obesity.45
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steatosis (first “hit”) that sensitizes the liver to oxidativestress (second “hit”).
Several agents have been identified as contributors to this oxidative stress: mitochondrial source of reactive ox-ygen species (ROS), increased lipid peroxidation, in-creased activity of the cytochrome P450 enzyme CYP2E1 and the effects of cytokines such as tumor ne-crosis factor alpha (TNF α), transforming growth factor beta (TGF-β) and interleukin 8 (IL-8).
Patients with NASH have been found to have structur-al mitochondristructur-al defects with associated deficiencies in the electron transport chain as well as increased lipid per-oxidation levels.47 In this setting of mitochondrial
abnor-mality and increase hepatic lipid FFA (per the mecha-nisms described above), there is increased production of ROS leading to lipid peroxidation. Lipid peroxidation products impair the flow of electrons along the respirato-ry chain, which increases ROS and the cycle repeats in-definitely.45,48 Cytokines have been implicated in
in-creased oxidative stress as well. Reactive oxygen species and lipid peroxidation products contribute to stimulating the release of inflammatory mediators such as TNF-α and TGF-β and IL-8 that in turn promote neutrophil infiltra-tion, fibrosis, Mallory bodies and hepatocyte death.44
Fatty acids are inducers of CYP2E1. One study dem-onstrated an increased in the expression of CYP2E1 in livers of patients with NASH. The pattern of distribution was predominantly around the terminal hepatic vein (zone 3); similar to the pattern of injury typically seen in NASH.49 Increased activity of CYP2E1 may result in
ox-idative stress through direct hepatocyte injury or recruit-ment of inflammatory cells.46
The pathogenesis of NAFLD remains highly specula-tive and our understanding of the above-described mech-anism is evolving. Elucidating the pathway from steatosis to inflammation, fibrosis and cirrhosis, will help in de-signing treatment protocols targeted at specific sites of pathogenesis.
Treatment
There is no established pharmacological treatment for NAFLD.
The effects of weight loss in patients with NAFLD re-main conflicting. In one study, 41 extremely obese pa-tients were monitored before and after losing a median of 34 kg. Fatty changes in the liver and liver biochemistry improved. However, 24% of the patients developed mild portal inflammation or fibrosis (only in the group with rapid weight loss).50 In a retrospective study of 39
over-weight patients, over-weight loss corresponded with improve-ment in biochemical markers. No histologic data was available in this population.51 The available information
supports the idea of gradual weight loss (initial goal: 10% of total body weight at six months), averaging about 1-2 pounds per week.52,53
Other treatment protocols focus on treating the associ-ated conditions such as diabetes and hyperlipidemia. However, control of diabetes and hyperlipidemia do not result in reversal of NAFLD.
A small number of pilot studies have attempted to evaluate the role of pharmacotherapy in controlling or re-versing NAFLD. Drugs studied include ursodeoxycholic acid (UDCA), clofibrate, vitamin E, metformin, betaine, and N-acetylcysteine.
UDCA is a hydrophilic dihydroxy bile acid. It has sev-eral properties that make it a desirable agent in the treat-ment of liver disease. UDCA variably decreases the con-centration of toxic endogenous bile acids, it has immuno-modulatory effects and it is protective to hepatocytes.54 In
one open-label trial, 24 patients were treated with 13-15 mg/kg/d of UDCA for twelve months. Most patients had a significant decrease in serum alkaline phosphatase, ALT, and GGT, with improvement in the grade of hepat-ic steatosis.55 Similar liver chemistry results were found
in two studies where patients were treated with UDCA 10 mg/kg/d for six months.56 Despite these good biochemical
outcome, unfortunately, there was no histologic data analysis in these two studies. The long-term benefit of UDCA is currently being investigated.
Clofibrate is an agent used for the treatment of hyper-lipidemia associated with high triglyceride levels. In one study, 16 patients with NASH and hypertriglyceridemia were place on Clofibrate 2 gm/d for twelve months. There was no significant change in serum liver tests com-pared to baseline at the time of entry into the study.55
Vitamin E has been observed to reduce oxidative stress, hence the rationale for treatment in NAFLD. In one small, open-label pilot study, 11 children diagnosed with NASH were treated with Vitamin E: 400 and 1,200 IU daily. Serum aminotransferase levels decreased signif-icantly during the 4-10 month study period, but returned to abnormal levels when patients elected to discontinue the medication.57
Metformin is an agent that improves hepatic insulin sensitivity. Therefore it is not surprising that it has been seen as a likely candidate for treatment of NAFLD, where insulin resistance is known to occur. Metformin reversed hepatomegaly, steatosis and abnormal aminotransferase in obese, leptin-deficient mice.58 In one open-label trial,
20 patients with NASH were treated with metformin 500 mg three times daily for 4 months. Six patients did not complete the trial and were used as controls. Those in the treatment arm experienced improvement in hepatic insu-lin sensitivity, significant reduction in aminotransferase levels (normalized in 50%) and 20% reduction in hepatomegaly.59 Trials involving metformin and other
hy-poglycemic agents are currently underway.
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hydrous solution 20 g/d was administered for 12 months.Six of seven patients had significant improvement in ami-notransferase levels. The degree of steatosis, fibrosis and necroinflammatory grade also improved.60 In a larger
pro-spective randomized double-blinded trial, 96 patients were treated with betaine glucoronate, diethanolamine glucoronate and nicotinamide ascorbate, while 95 pa-tients were randomized to placebo. There was significant reduction in serum AST, ALT and GGT in the treatment group. In addition, there was a 25% reduction in steatosis and 6% reduction in hepatomegaly in those treated.61 This
study included more patients but is limited by a short treatment duration and the lack of histology.
N-acetylcysteine (NAC) is a glutathione precursor that increases the stores of glutathione and act as a substrate for toxic metabolites. Preliminary results of one study of 11 patients treated with NAC 1 g/d for 3 months, showed improvement in aminotransferase levels.62 As with some
other studies, this was of a short duration with few pa-tients and no histologic data. Therefore, validation through larger studies is needed.
Other classes or drugs such as the thiazolidinediones have been studied, revealing promising preliminary re-sults. However, further large controlled studies are need-ed before recommendations can be issuneed-ed.
Cryptogenic cirrhosis is the third leading cause of orthotopic liver transplant (OLT) in the United States (based on OPTN data as of October 2003).63 It is now
proposed that up to half of the cases designated as crypto-genic, may indeed be attributed to NASH cirrhosis. How-ever, the precise number of patients undergoing orthoto-pic liver transplant secondary to NASH induced liver failure remains uncertain. This may be explained in part, by the fact that some patients with end-stage NAFLD may have a “burned out” histology and so are sometimes classified as unknown etiology or cryptogenic cirrhosis.64
In addition, earlier cases of NASH may have gone unrec-ognized due to a lack of familiarity with this clinico-pathologic syndrome. Therefore, studies evaluating the relationship between NASH and liver transplantation are mostly retrospective and rely on clinical syndrome corre-lation for the “diagnosis” of NASH. Two studies illus-trate this point. One study reviewed 27 patients with cryptogenic cirrhosis and a “clinical histological pheno-type of NASH” and 3 patients with a known diagnosis of NASH. After a five-year follow up, all 27 assessable pa-tients (1 patient died perioperatively, 2 died later of sep-sis) had recurrent steatosis in the allograft (compared to 25% in the control group with pre-OLT diagnosis of pri-mary biliary cirrhosis and pripri-mary sclerosing cholangi-tis). Three patients had progression from steatosis to ste-atohepatitis (one of these developed progressive fibro-sis).65 Another series identified eight patients (of 622
cases) transplanted for NASH. Subjects were followed for up to four years. Six patients had recurrent fatty liver (3 with NASH).66 Orthotopic liver transplantation may
play an increasing role in the management of NAFLD. Even though it is not a direct treatment for NAFLD, but a salvage strategy for those who progress to liver failure.
In Summary non alcoholic fatty liver disease encom-passes a wide spectrum of disorders. Those with simple steatosis tend to remain stable over many years. However, those with the more advanced form of the disease (steato-sis with inflammation and fibro(steato-sis) tend to progress more rapidly to cirrhosis and end stage liver disease. Its associ-ation with type II diabetes mellitus and obesity portend an epidemic of NAFLD, as the number of obese and diabetic patients is increasing at alarming rates. Therefore, it is important to develop reliable, non-invasive diagnostic tools and predictors of the disease to determine which pa-tients will be in need of more aggressive intervention. Ini-tial pilot studies show some promise of treatment options. However, in order to make generalized recommendations about treatment and prognosis, larger well-controlled clinical trials of prolonged duration are necessary.
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